Molecular pathways associated with BCC to SCC pathway switching

与 BCC 至 SCC 途径转换相关的分子途径

• 批准号: 10441284
• 负责人: Daniel William Haensel
• 金额: $ 1.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441284
• 关键词: ATAC-seq; Address; Automobile Driving; Award; Basal cell carcinoma; Binding; Binding Sites; Biopsy; Cancer Biology; Cell surface; Cells; ChIP-seq; Chromatin; Clinical; Combined Modality Therapy; Complex; Computational Technique; Coupling; Data; Data Set; Dependence; Development; Diagnosis; Epigenetic Process; Epithelial; Erinaceidae; Event; Evolution; Family; Family member; Fibrinogen; Funding; GLI gene; Gene Expression; Generations; Genetic; Genetic Transcription; Genomics; Goals; Growth; Health; Human; In Vitro; Investigation; JUN gene; Knowledge; Lead; MAP Kinase Gene; Modeling; Molecular; Mus; Mutation; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Process; RNA Interference; Regulation; Research; Resistance; Resolution; SHH gene; Sampling; Scientist; Signal Pathway; Site; Skin Cancer; Squamous cell carcinoma; System; Testing; Therapeutic; Time; Training; Transcription Factor AP-1; Transcriptional Regulation; Transplantation; Viral; Work; base; cancer therapy; cancer type; career; combinatorial; design; epigenetic regulation; epigenomics; experimental study; genetic signature; in vitro Model; in vivo; inhibitor; innovation; insight; mouse model; multiple omics; non-drug; novel; overexpression; prevent; programs; resistance mechanism; single-cell RNA sequencing; targeted treatment; tool; transcription factor; tumor; tumor heterogeneity; tumor progression

PROJECT SUMMARY/ABSTRACT: Basal cell carcinoma (BCC) represents the most common type of skin cancer with more than four million cases in the US each year. BCCs have the ability to circumvent therapeutics due to their intrinsic tumor plasticity, allowing for incredible tumor evolution. The identification of non-canonical pathways that drive tumor resistance has dramatically impacted the understanding of BCC resistance mechanisms, however, the complex tumor heterogeneity generates a significant knowledge gap, which continues to hamper clinical outcomes. The observation that BCCs can undergo tumor evolution events (referred to as pathway switching) to squamous cell carcinoma (SCC) represents a resistance mechanism involving complete alterations in gene expression programs leading to cancer-type switching. The long-term goal of this proposal is to elucidate the molecular and transcriptional mechanisms underlying pathway switching with particular emphasis on understanding the epigenetic regulation at single cell resolution. Preliminary data indicate that SCC-signatures develop early in tumor progression, which is in part due to differential transcriptional regulation of AP-1 family members, but what specific transcription factor is not clear. Therefore, the central hypothesis underlying this proposal is that dynamic epigenetic regulation promotes the acquisition of SCC-like features in BCCs, potentially early on in tumor development. Aim 1 will uncover the key AP-1 family transcription factor(s) that drive BCC to SCC pathway switching utilizing a novel in vitro system which can faithfully model this process. Aim 2 takes advantage of scRNA-Seq datasets from naïve tumors and proposes additional scRNA-Seq along with scATAC-Seq experiments to define a multi-omic temporal progression of BCC to SCC pathway switching. With a pipeline to acquire fresh human BCC tumors established and the ability to leverage expertise in single-cell genomic analysis, the proposed research is highly feasible in the allotted time. The overall rationale for the proposal is to adequately address a clinically unmet need to understand a key resistant mechanism in BCC. This highly innovative proposal uses novel tools, coupling an in vitro system to model pathway switching with single cell gene expression and chromatin analysis of patient samples. This work has great promise to fill a significant knowledge gap concerning mechanisms of BCC tumor evolution with goals to clear the path for more targeted and rationale drug therapies.

项目总结/摘要： 基底细胞癌（BCC）是最常见的皮肤癌类型，有超过400万例病例 每年在美国。BCC由于其固有的肿瘤可塑性而具有避开治疗剂的能力， 让肿瘤发生了惊人的进化识别驱动肿瘤耐药的非经典途径 极大地影响了对BCC耐药机制的理解，然而，复杂的肿瘤 异质性产生了显著的知识差距，这继续阻碍临床结果。的 观察到BCC可以经历肿瘤演变事件（称为途径转换）， 细胞癌（SCC）代表了一种涉及基因表达完全改变的耐药机制 导致癌症类型转换的项目。这项提案的长期目标是阐明 和转录机制的基础途径转换，特别强调了解 单细胞分辨率的表观遗传调控。初步数据表明，SCC-签名开发早在 肿瘤进展，这部分是由于AP-1家族成员的差异转录调控，但 具体是什么转录因子还不清楚。因此，这一提议的核心假设是， 动态表观遗传调节促进BCC中SCC样特征的获得，可能在早期 肿瘤发展目的1将揭示关键的AP-1家族转录因子驱动BCC SCC 通路转换利用一种新的体外系统，可以忠实地模拟这一过程。目标2采取 scRNA-Seq数据集的优势，并提出了额外的scRNA-Seq沿着 scATAC-Seq实验定义BCC至SCC途径转换的多组学时间进程。与 建立了获取新鲜人类BCC肿瘤的管道，并能够利用单细胞 基因组分析，拟议的研究是高度可行的，在规定的时间。总体理由是， 建议是充分解决临床上未满足的需要，以了解BCC的关键耐药机制。 这个高度创新的提案使用新颖的工具，将体外系统与模型途径转换结合起来， 单细胞基因表达和染色质分析。这项工作有很大的希望填补一个 关于BCC肿瘤演变机制的重大知识差距，目标是为以下目标扫清道路： 更有针对性和合理性的药物治疗。

项目成果

c-FOS drives reversible basal to squamous cell carcinoma transition.

• DOI: 10.1016/j.celrep.2021.109774
• 发表时间: 2021-10-05
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Kuonen F;Li NY;Haensel D;Patel T;Gaddam S;Yerly L;Rieger K;Aasi S;Oro AE
• 通讯作者: Oro AE

AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma.

• DOI: 10.1038/s41467-020-18762-5
• 发表时间: 2020-10-08
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Yao CD;Haensel D;Gaddam S;Patel T;Atwood SX;Sarin KY;Whitson RJ;McKellar S;Shankar G;Aasi S;Rieger K;Oro AE
• 通讯作者: Oro AE

LY6D marks pre-existing resistant basosquamous tumor subpopulations.

• DOI: 10.1038/s41467-022-35020-y
• 发表时间: 2022-12-06
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Haensel, Daniel;Gaddam, Sadhana;Li, Nancy Y;Gonzalez, Fernanda;Patel, Tiffany;Cloutier, Jeffrey M;Sarin, Kavita Y;Tang, Jean Y;Rieger, Kerri E;Aasi, Sumaira Z;Oro, Anthony E
• 通讯作者: Oro, Anthony E